Abstract The objective of this study was to compare reproductive and economic efficiency between the estrus synchronization protocols utilizing a controlled internal drug release insert (CIDR-E2-PG) and fixed time artificial insemination protocol (Ovsynch) in lactating cows. A total of 120 anestrus cross-breed Holstein Frisian lactating cows from 9 dairy herds were randomly assigned to the CIDR-E2-PG (n=60) or the Ovsynch (n=60) protocol. Overall, the cumulative pregnancy rate within 250 d in milk period, cows in the CIDR-E2-PG group tended to have a higher (P=0.14) compared with the cows received Ovsynch program. Cows in the CIDR-E2-PG group tended to have a greater percentage of pregnancy within the first AI (P=0.11). Irrespective of lactation number and body condition score, estimated median times of day open of cows in the CIDR-E2-PG group tended to be (P=0.07) a shorter than the Ovsynch cows. The cost per conception utilizing the CIDR-E2-PG protocol was lower than the Ovsynch protocol. Furthermore, the efficient scale of economics for the CIDR-E2-PG protocol was significantly higher (P<0.05) when compared with the Ovsynch protocol. It can be concluded that estrus synchronization with the CIDR-E2- PG protocol tended to improve reproductive performances, reduced production cost and increase the economic efficiency scale in lactating cows.